Process for preparation of citalopram and enantiomers

ABSTRACT

The present invention provides a process for preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile comprising reacting a compound of formula IVa, in the presence of a base with a compound of formula RX, 
     
       
         
         
             
             
         
       
         
         
           
             wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which may be optionally substituted with electron withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and OR 1 , wherein Tf represents trifluoromethanesulfonyl group, and R 1  is optionally substituted alkyl, Z is a cyano group or a group that may be converted to a cyano group; 
             further wherein RX is selected such that an intermediate ether derivative, a compound of formula Va formed from said reaction cyclizes to a compound of formula VI, 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             and where Z is not a cyano group, conversion of the group Z in the compound of formula VI to a cyano group to form 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile. The present invention also provides novel ether compound, a compound of formula Va and a process for preparation thereof.

The invention provides a process for preparation of(RS)-(±)-1-[3-(di-methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranbonitrile (a compound of formula I, INN name for the compound iscitalopram) and its enantiomers viz.,(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (a compound of formula II, known as (S)-(+)-citalopram orescitalopram) and(R)-(−)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (a compound of formula III) and acid addition saltsthereof.

More particularly, the invention provides a process for preparation ofcitalopram or its enantiomers via novel ether intermediate compounds.

Citalopram was first disclosed in U.S. Pat. No. 4,136,193 and(S)-(+)-citalopram in U.S. Pat. No. RE 34,712 (the '712 patent).

U.S. Pat. No. 4,650,884 teaches use of the diol, viz.,4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxylmethyl)-benzonitrile,a compound of formula IV in racemic form, which is cyclized in presenceof H₂SO₄ to obtain citalopram (Scheme I).

The '712 patent teaches preparation of (S)-(+)-citalopram, a compound offormula II by using the enantiomeric diol compound of formula IV, viz.,(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile,which is derivatized to obtain a labile ester thereof likemethanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetylor trifluoromethanesulfonyl. The labile ester derivative is cyclizedstereoselectively, in presence of a base to obtain the (+)-isomer,namely (S)-(+)-citalopram (Scheme II).

The prior art strategies are based on cyclization of the diol underacidic conditions to obtain citalopram or derivatization through alabile ester derivative and cyclization in presence of a base to obtain(S)-(+)-citalopram. These processes of prior art have followingdisadvantages when the process is to be scaled-up for industrial use:

-   -   1. Cyclization of the diol at higher temperature using acids        generates amide, acid, indene by-products leading to formation        of impure product.    -   2. Use of the labile esters demonstrated for making enantiomers        of citalopram requires use of a reactive agents like        methanesulfonyl chloride which could give rise bismesylates and        thus could lead to the formation of undesired impurities.    -   3. For preparation of the labile esters, organic bases like        triethylamine, pyridine are used as proton scavengers, the        undesired labile esters of tertiary alcohol group formed under        the reaction condition can proceed via non-concerted manner        resulting in chirality perturbation and impurity formation. The        excess of base employed can also participate in displacing the        reactive ester to form the corresponding ammonium derivatives        due to its inherent nucleophilicity.    -   4. The labile ester is sensitive to moisture, temperature,        resulting in decomposition.

There is a need for a convenient, robust process for efficientpreparation of citalopram and enantiomers thereof. The present inventionprovides such a process for preparation of citalopram and enantiomersthereof by use of the racemic or enantiomeric diol intermediate, whichis derivatized to obtain an ether derivative thereof, which can becyclised in-situ to obtain citalopram or enantiomers thereof. The etherderivatives are formed at the primary alcohol group of the diolintermediate by reacting with aryls, heteroaryls or alkyls optionallysubstituted with electron withdrawing groups.

The present invention provides a process for preparation of citalopramor enantiomers thereof, particularly, (S)-(+)-citalopram of desiredenantiomeric purity.

SUMMARY OF THE PRESENT INVENTION

The present invention provides a process for preparation of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile comprising reacting a compound of formula IVa, in thepresence of a base with a compound of formula RX,

wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which maybe optionally substituted with electron withdrawing groups and X isselected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf representstrifluoromethanesulfonyl group, and R₁ is optionally substituted alkyl,Z is a cyano group or a group that may be converted to a cyano group;further wherein RX is selected such that an intermediate etherderivative, a compound of formula Va formed from said reaction cyclizesto a compound of formula VI,

and where Z is not a cyano group, conversion of the group Z in thecompound of formula VI to a cyano group to form1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

The present invention in one embodiment provides a process forpreparation of1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile comprising reacting4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile,in the presence of a base, with a compound of formula RX, wherein R isselected from alkyl, alkenyl, aryl and heteroaryl which may beoptionally substituted with electron withdrawing groups and X isselected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf representstrifluoromethanesulfonyl group, and R₁ is optionally substituted alkyl;further wherein RX is selected such that an intermediate etherderivative, a compound of formula V formed from said reaction,

cyclizes to1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

The present invention provides novel ether compound, a compound offormula Va, or acid addition salt thereof,

wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which maybe optionally substituted with electron withdrawing groups and Z is acyano group or a group that may be converted to a cyano group.

The present invention in one embodiment provides novel ether compound, acompound of formula V or acid addition salt thereof,

wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which maybe optionally substituted with electron withdrawing groups.

The present invention provides a process for preparation of a compoundof formula Va, comprising reacting a compound of formula IVa, in thepresence of a base with a compound of formula RX,

wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which maybe optionally substituted with electron withdrawing groups and X isselected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf representstrifluoromethanesulfonyl group, and R₁ is optionally substituted alkyl,Z is a cyano group or a group that may be converted to a cyano group.

The present invention in one embodiment provides a process forpreparation of a compound of formula V,

comprising reacting4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile,in the presence of a base, with a compound of formula RX,wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which maybe optionally substituted with electron withdrawing groups and X isselected from F, Cl, Br, I, CN, OTf and OR1, wherein Tf representstrifluoromethanesulfonyl group, and R1 is optionally substituted alkyl.

DETAILS OF THE PRESENT INVENTION

As used herein1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile may represent a racemic or an enantiomeric compound,especially (S)-(+)-isomer thereof, unless otherwise specified.

The compound of formula IVa, the compound of formula Va or the compoundof formula VI represents a racemic or an enantiomeric compound, unlessotherwise specified.

Z is a cyano group or a group that may be converted to a cyano group.Such groups, Z, may be selected from halogen, —OH, —CHO, —CH₂OH,—CH₂NH₂, —CH₂NO₂, —CH₃, —CH₂Cl, —CH₂Br, —NHR₂, —COOR₃, —CONR₃R₄,CF₃—(CF₂)_(n)—SO₂—O— wherein n is 0-8, R₂ is hydrogen or C1 to C6alkylcarbonyl and R₂ and R₃ are selected from hydrogen, optionallysubstituted C1 to C6 alkyl or aryl and, a group of formula VII:

wherein Y is O or S; R₅ and R₆ are each independently selected fromhydrogen and C1 to C6 alkyl or R₅ and R₆ together form a C2 to C5alkylene chain thereby forming a spiro ring; R₇ is selected fromhydrogen, C1 to C6 alkyl, R₈ is selected from hydrogen, C1 to C6 alkyl,a carboxy group or a precursor group thereof, or R₇ and R₈ together forma C2 to C5 alkylene chain thereby forming a spiro ring.

When Z is halogen, in particular bromo or chloro, conversion of thecompound of formula VI to form1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile may be carried out by any process as known in the art, forexample as described in U.S. Pat. No. 4,136,193, PCT publications WO00/13648, WO 00/11926 or WO 01/02383.

Compounds of formula VI, wherein the group Z is CF₃—(CF₂)_(n)—SO₂—O—,wherein n is 0-8, may be converted to1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile by methods analogous to those described in PCT publicationWO 00/13648.

Compounds of formula VI, wherein the group Z is —CHO, may be convertedto1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile by methods analogous to those described in PCT publicationWO 99/30548.

Compounds of formula VI, wherein the group Z is —NHR₂, wherein R₂ ishydrogen or alkylcarbonyl, may be converted by to1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile by methods analogous to those described in PCT publicationWO 98/19512.

Compounds of formula VI, wherein the group Z is —COOR₃ or —CONR₃R₄,wherein R₃ and R₄ are selected from hydrogen and optionally substitutedalkyl or aryl may be converted to1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile by methods analogous to those described in PCT publicationsWO 98/19511 and WO 98/19513.

Compounds of formula VI, wherein the group Z is a group of formula VIImay be converted to1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile by methods analogous to those described in PCT publicationWO 00/23431.

Compounds of formula VI, wherein Z is OH, —CH₂OH, —CH₂NH₂, —CH₂NO₂,—CH₂Cl, —CH₂Br, —CH₃ or any of the groups above, may be converted to1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile by methods analogous to those described in PCT publicationsWO 01/68632 and WO 01/85712.

Starting materials of formula IVa may be prepared according to the abovementioned patents and patent applications, which are incorporated hereinby reference or by analogous methods known in the art.

The compound RX is a compound, which can react with a compound offormula IVa such as,4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrileto form a ether derivative, a compound of formula Va, viaaddition-elimination type reaction, X being any suitable leaving group.A suitable leaving group is any group which upon reaction of a compoundof formula IVa with the compound RX, facilitates formation of an etherderivative represented by a compound of formula Va.

In a preferred embodiment RX is a compound of formula, wherein R isselected from alkyl, alkenyl, aryl and heteroaryl which may beoptionally substituted with electron withdrawing groups and X isselected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf representstrifluoromethanesulfonyl group, and R₁ is alkyl optionally substitutedwith electron withdrawing groups.

RX is further selected from compounds capable of forming an etherderivative, a compound of formula Va.

In the process of the invention, a compound of formula Va is formed byreaction of compound of formula IVa with a compound of formula RX, inpresence of a base. The compound of formula Va can in-situ cyclize toform a compound of formula VI. If desired it can be isolated and thensubjected to cyclization in presence of a base.

In a preferred embodiment, the ether derivative compound of formula V,formed by reaction of4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrilewith a compound of formula V, in presence of a base, cyclizes in-situ todirectly form1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile. However, if it is so desired, the ether derivativecompound of formula V may be isolated and subjected to cyclization inpresence of a base.

Further, preferably, the compound RX is not labile like methanesulfonylchloride used in the prior art, the '712 patent, and thus resulting inan advantage of easier handling and storage and leading to preparationof chirally pure S-(+)-citalopram end product. The use ofmethanesulfonyl chloride may give rise to bismesylates leading toformation of undesired impurities with chirality perturbation.

The present invention provides novel ether compound, a compound offormula Va, or acid addition salt thereof,

and a process for preparation thereof comprising reacting a compound offormula IVa, in the presence of a base, with a compound of formula RX,wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which maybe optionally substituted with electron withdrawing groups and X isselected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf representstrifluoromethanesulfonyl group, and R₁ is optionally substituted alkyl,Z is a cyano group or a group that may be converted to a cyano group.

The present invention in one embodiment provides novel ether compound, acompound of formula V, or acid addition salt thereof,

and a process for preparation thereof comprising reacting4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxylmethyl)-benzonitrile,in the presence of a base, with a compound of formula RX,

wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which maybe optionally substituted with electron withdrawing groups and X isselected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf representstrifluoromethanesulfonyl group, and R₁ is optionally substituted alkyl.

In a preferred embodiment, the present invention provides4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)-benzonitrile,a compound of formula VIII, or acid addition salt thereof,

and a process for preparation thereof comprising reacting4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxyl-methyl)benzonitrile,in the presence of a base, with 2,5-dichloronitrobenzene.

In a more preferred embodiment, the present invention provides novel(S)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxy-methyl)-benzonitrileor an acid addition salt thereof for example, hydrochloride salt.

In a particularly preferred embodiment, the present invention provides(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxy-methyl)-benzonitrilehydrochloride.

The acid addition salt of compound of formula V, Va or VIII may beprepared by any standard method of contacting the compound of formula V,Va or VIII with an acid, for example inorganic acid like hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid andthe like or organic acid like oxalic acid, citric acid, succinic acid,cinnamic acid, p-toluenesulfonic acid and the like.

As used herein, “alkyl” may be any straight, branched, or cyclic alkylgroup of C1 to C6 atoms, optionally substituted with one or moreelectron withdrawing groups selected from nitro, halo, cyano,4-trifluoroalkyl, 2,4-bis(trifluoroalkyl), 2,6-bis(trifluoroalkyl),—CHO, —COOR₉, wherein R₉ may be alkyl, aryl or heteroaryl.

As used herein, “alkenyl” may be any straight, branched, or cyclic alkylgroup of C1 to C6 atoms, optionally substituted with one or moreelectron withdrawing groups selected from nitro, halo, cyano,4-trifluoroalkyl, 2,4-bis(trifluoroalkyl), 2,6-bis(trifluoroalkyl),—CHO, —COOR₉, wherein R₉ may be alkyl, aryl or heteroaryl.

As used herein, “aryl” may be a mono-, bi- or polycyclic aromaticsystem, for example phenyl, naphthyl, optionally substituted with one ormore electron withdrawing groups selected from nitro, halo, cyano,4-trifluoroalkyl, 2,4-bis(trifluoroalkyl) or 2,6-bis(trifluoroalkyl),—CHO, —COOR₉, wherein R₉ may be alkyl, aryl or heteroaryl.

As used herein, “heteroaryl” may be a mono-, bi- or polycyclic aromaticsystem containing one or more hetero atom which may be same ordifferent, for example quinolinyl, isoquinolinyl, pyridinyl, indanyl,fluorenyl, oxazolyl, pyrazinyl, thienyl, quinazolinyl, benzimidazolyland the like optionally substituted with one or more electronwithdrawing groups selected from nitro, halo, cyano, 4-trifluoroalkyl,2,4-bis(trifluoroalkyl) or 2,6-bis(trifluoroalkyl), —CHO, —COOR₉,wherein R₉ may be alkyl, aryl or heteroaryl.

As used herein, “hetero atom” may preferably be selected from N, O, S orP.

The base used may be selected from an alkoxide, wherein the alkylresidue is C1 to C6 linear, branched or cyclic alkyl and the counter ionis an alkali or alkaline earth metal; alkali or alkaline earth metaloxide, hydroxide, carbonate or bicarbonate or an amine base. The aminebase may be selected from aliphatic or aromatic amines, cyclic oracyclic amines, for example isoquinolines, quinolines,dialkylarylamines, pyridine, substituted pyridines. The base may beselected from moderate bases that do not favor the formation ofbisalkoxides thus providing control over the derivatization of theprimary alcohol group of the diol.

The ether derivative compounds represented by a compound of formula V orVa can cyclize to form citalopram or enantiomers thereof. When the diolcompound, viz., a compound of formula IV or IVa is used in enantiomericform, derivatized to form an ether derivative thereof, a compound offormula V or Va, it cyclizes stereoselectively to affordenantiomerically pure citalopram.

In a preferred embodiment, the group R is:

wherein one or more of a, b and c may be carbon or hetero atom which maybe same or different, P and Q may be selected from electron withdrawinggroups like NO₂, CF₃, CN, halogen, COOR₉, CHO and the like, wherein R₉is alkyl, aryl or heteroaryl.

In another preferred embodiment the compound of formula RX is selectedfrom the group consisting of the following compounds:

In one embodiment the present invention provides a process forpreparation of racemic1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile comprising reacting racemic4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile,with a compound of formula RX, in presence of a base. Preferably thecompound of formula RX is dichloronitrobenzene.

In another embodiment the present invention provides a process forpreparation of enantiomeric1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile comprising reacting enantiomeric4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile,with a compound of formula RX, in presence of a base. Preferably thecompound of formula RX is dichloronitrobenzene.

In another preferred embodiment the present invention provides a processfor preparation of(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile comprising reacting(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxylmethyl)-benzonitrile,with a compound of formula RX, in presence of a base. Preferably thecompound of formula RX is dichloronitrobenzene.

In a particularly preferred embodiment the present invention provides aprocess for preparation of(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile comprising reacting(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrilewith 2,5-dichloronitrobenzene, in presence of a base to form a compoundof formula VIII,

and cyclization of compound of formula VIII.

The process of the present invention may be carried out in any suitablesolvent. Examples of solvents that may be used are alcohol solvents likemethanol, ethanol, t-butanol, polyethyleneglycol; ketone solvents likeacetone, methyl iso-butyl ketone; ether solvents like tetrahydrofuran,dioxane; ester solvents like ethylacetate, butylacetate; amide solventslike dimethylformamide, dimethylacetamide; nitrile solvents likeacetonitrile; dipolar aprotic solvents like dimethylsulfoxide,sulfolane; hydrocarbon and aromatic hydrocarbon solvents having aboiling point greater than 70° C.

The process of the present invention can be carried out in a suitablesolvent with a base at temperature ranging from ambient to the refluxtemperature of the selected solvent. The reaction may be completed in0.5 to 40 hours, preferably 0.5 to 20 hours depending on the selectedsolvent and base.

In a typical procedure, the reaction may be worked-up by quenching byaddition of 2 to 10 volumes, preferably 3 to 8 volumes of water to thereaction solvent, depending on the product solubility in the selectedsolvent, at temperature between the range of 0° C. to 100° C.,preferably 20° C. to 60° C. The reaction mixture may be extracted with asuitable water-immiscible solvent like toluene, ether, ethylacetate.

If desired,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile may be converted to a pharmaceutically acceptable acidaddition salt thereof by treatment with organic or inorganic acid.Examples of organic acids are oxalic, fumaric, succinic mandelic,benzoic, p-toluenesulfonic acid and the like. Examples of inorganicacids are hydrobromic, hydrochloric, sulfuric, phosphoric, nitric andthe like. The preparation of salt formation may be carried out in asolvent like acetone, water, methanol, isopropanol, dimethylformamide ormixture thereof.

The worked out examples given below illustrate the process and not to beconstrued as limiting.

EXAMPLES Example 1 Preparation of Citalopram Oxalate

To a solution of 10 gm of(RS)-(±)4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrilein 50 ml of dimethylsulfoxide (DMSO) at room temperature was added 12 gmof anhydrous K₂CO₃ and 6.73 gm of 2,5-dichloronitrobenzene was added tothe above reaction mixture at room temperature and stirred at 100° C.for 15 hours. To the reaction mixture, 250 ml of water was added andextracted with toluene, the toluene layer was washed with water and 5%sodium hydroxide solution and after acid base treatment yielded an oilyproduct. The oil was dissolved in 40 ml of acetone at 30° C. and 3.4 gmof oxalic acid dihydrate was added to it, stirred, cooled, filtered anddried at 60° C.

Dry wt: 7.8 gm.

Example 2 Preparation of (S)-(+)-citalopram oxalate

To a solution of 6 gm of(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethylbenzoate)-benzonitrilein 60 ml tetrahydrofuran (THF) was added 4.33 gm of potassium tertiarybutoxide at 0-10° C. and stirred for 30 minutes. A solution of 4.04 gmof 2,5-dichloronitrobenzene in 30 ml THF at 0-10° C. was added to it andstirred for 10-15 hours at room temperature, followed by addition of 250ml of water. The reaction mixture was extracted with toluene, thetoluene layer was washed with water and 5% sodium hydroxide solution andafter acid base treatment yielded an oily product. The oil was dissolvedin 16 ml of acetone at 30° C. and 1.75 gm of oxalic acid dihydrate in 8ml acetone was added to it, stirred, cooled, filtered and dried at 60°C. to get the oxalic acid salt of(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

Dry wt: 4.3 gm, [α]_(D)=+11.8° (c=1, methanol).

Chiral HPLC: R-isomer content: 0.64%

Example 3 Preparation of (S)-(+)-citalopram oxalate

To a solution of 6.0 gm of(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrilein 30 ml of DMSO at room temperature was added 7.3 gm of anhydrous K₂CO₃and 4.04 gm of 2,5-dichloronitrobenzene was added to the above reactionmixture at room temperature and stirred at 100° C. for 15.0 hours. Tothe above reaction mixture, 120 ml of water was added, and extractedwith toluene. The toluene layer was washed with water and 5% sodiumhydroxide solution and after acid base treatment yielded an oilyproduct. The oil was dissolved in 16 ml of acetone at 30° C. and 1.9 gmof oxalic acid dihydrate in 8 ml of acetone was added to it, stirred,cooled, filtered and dried at 60° C.

Dry wt: 4.1 gm, [α]_(D)=+12.62° (c=1, methanol).

Chiral HPLC: R-isomer content: 0.2%

Example 4 Preparation of (S)-(+)-citalopram oxalate

To a solution of 64 Kg of(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethylbenzoate)-benzonitrilein 300 lit DMSO was added 77.48 Kg of anhydrous K₂CO₃ and 43.06 Kg of2,5-dichloronitrobenzene at room temperature and stirred for 16 hours at100-105° C. To the reaction mixture 3000 ml of water was added at about30° C. The reaction mixture was extracted with toluene, the toluenelayer was washed with water and 5% sodium hydroxide solution and afteracid base treatment yielded an oily product. The oil was dissolved in510 lit of isopropanol at about 30° C. and 20.4 lit water added, stirredfor 10 minutes and 20.8 Kg of oxalic acid dihydrate was added and heatedto about 70-75° C., stirred, charcolised, cooled and filtered. Thefiltrate was cooled to 5-10° C. slowly and the resultant solid wasfiltered, dried at 60° C. and micronised to get the oxalic acid salt of(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

Dry wt: 61.5 Kg, [α]_(D)=+13.85° (c=1, methanol).

Chiral HPLC: R-isomer content: 0.38%.

Purity by HPLC: 99.25%.

Example 5 Preparation ofS-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)-benzonitrilehydrochloride

To a solution of 5.6 gm of(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrilein 85 ml THF was added 2.02 gm of potassium tertiary butoxide at 0-10°C. and stirred for 10 min. 3.14 gm of 2,5-dichloronitrobenzene was addedto the reaction mixture at 0-10° C. and stirred for 10-15 hrs at RT(30-35° C.), solvent distilled under vacuum and 40 ml of water wasadded, and extracted with toluene, toluene layer was washed with waterand 10% sodium hydroxide solution and distilled to get an oily product,which is purified by column chromatography using silica gel andethylacetate, Wt: 500 mg.

The above oily product was dissolved in 10 ml of isopropanol (IPA) at30° C. and 2.0 ml of IPA-HCl was added, stirred and solvent distilledunder vacuum and crystallized in IPA to get(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrilehydrochloride whose structure was confirmed by IR, NMR and Mass spectraldata.

Dry wt: 300 mg, [α]_(D)=46.8° (c=1, methanol).

Analysis calculated for C26H26N3O4Cl2F: C, 58.44; H, 4.90; N, 7.86;found: C, 57.42; H, 4.65; N, 7.33.

¹HNMR (400.13 MHz, DMSO-d6) δ1.42-1.43 (broad m, 1H); 1.75-1.76 (broadm, 1H); 2.32-2.47 (m, 2H); 2.70 (s, 6H); 3.00-3.13 (m, 2H); 5.03 (d,J=14.01 Hz, 1H); 5.43 (d, J=14.04 Hz, 1H); 6.43 (s, 1H); 6.52 (d, J=9.09Hz, 1H); 7.18 (t, J=8.85 Hz, 2H); 7.39 (dd, J₁=8.71 Hz, J₂=5.41 Hz, 2H);7.54 (dd, J₁=8.97 Hz, J₂=2.63 Hz, 1H); 7.90 (s, 1H); 7.96 (d, J=8.25 Hz,1H); 8.03 (d, J=8.25 Hz, 1H); 8.08 (d, J=2.63 Hz, 1H); 10.36 (s, 1H).

¹³CNMR (100.61 MHz, DMSO-d6) δ18.44 (t); 38.87 (t); 41.86 (2q); 56.47(t); 67.83 (t); 76.63 (s); 110.49 (s); 114.84 (2d, J=21.23 Hz); 116.11(d); 124.93 (d); 118.48 (s); 124.17 (s); 127.57 (d); 127.88 (2d, J=8.02Hz); 130.99 (d); 131.31 (d); 133.84 (d); 136.47 (s); 139.55 (s); 140.89[s(d, J=2.80 Hz)]; 149.27 (s); 149.45 (s); 160.91 [s(d, J=243.67 Hz)].

Mass: CI Mode, M⁺=498.20 (0.87%); (M-173)=325.30 (100.0%).

IR (KBr): cm-¹ 735.02, 747.45; 1162.70, 1230.44; 1507.93, 1603.51;1283.12, 1528.82; 2226.34; 2935.53, 3039.88, 3062.31; 3249.93.

Example 6 Preparation of (S)-(+)-citalopram

To a solution of 100 mg of(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)benzonitrilehydrochloride in 2.0 ml of DMSO was added 64.5 mg of potassium carbonateat 30-35° C. and stirred for 30 min at 95-100° C. After reactioncompletion which is monitored by TLC, 40 ml of water was added, andextracted with toluene, toluene layer was washed with water and 10%sodium hydroxide solution and distilled out toluene to get an oilyproduct.

Wt: 65.0 mg

Chiral HPLC: S-isomer content: 100%.

¹HNMR (400.13 MHz, CDCl₃) δ1.27-1.38 (m, 1H); 1.41-1.53 (m, 1H); 2.13(s, 6H); 2.09-2.25 (m, 4H); 5.15 (d, J=12.96 Hz, 1H); 5.19 (d, J=12.96Hz, 1H); 6.98-7.02 (m, 2H); 7.38-7.49 (m, 4H); 7.58 (d, J=7.77 Hz, 1H).

Example 7 Preparation of (S)-(+)-citalopram

Given Below in Table I is the Comparison Between (S)-(+)-citalopramOxalate Prepared by:

A] the prior art process using the methanesulfonyl ester derivative(Experiments A(1), A(2) and A(3)) and B] the process of the presentinvention using the ether derivative compound VIII (Experiments B(1),B(2) and B(3)):

TABLE I (S)-(+)-citalopram oxalate Chiral HPLC Input Batch purity %Specific optical HPLC Experiment No. of the S- R- rotation Unknown No.Batch No. starting diol isomer isomer (1% methanol) Purity % impurity %A(1) 1511- PN 42701 98.96 1.04 +13.1° 99.59 0.18 S/F/771/15 A(2) 1511-PN 41864 99.16 0.84 +13.0° 99.69 0.09 S/F/771/16 A(3) 1511- 1511- 99.150.85 +12.9° 98.95 0.6 S/F/771/20 S/II/771/10A B(1) 1511- PN 42701 99.660.34 +13.2° 99.76 0.05 S/F/771/17 B(2) 1511- PN 41864 99.62 0.38 +13.1°99.77 0.05 S/F/771/18 B(3) 1511- 1511- 99.77 0.23 +13.4° 99.76 0.03S/F/771/19 S/II/771/10AExperiment A(1):

To a solution of 16 gm of(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethylbenzoate)-benzonitrilein 128 ml dichloromethane was added 14.2 gm of triethylamine, stirredand cooled and 8.0 gm of methanesulfonylchloride was added at below 10°C. and stirred at less than 10° C. for 1.0 hr. To the reaction mixture65 ml of water was added and extracted with dichloromethane. Thedichloromethane layer was washed with water and distilled and dissolvedthe material in toluene, the toluene layer was washed with water anddistilled to get an oily product. The oil was dissolved in 50 ml acetoneand 5.12 gm of oxalic acid dihydrate in 50 ml acetone was added to it atroom temperature, stirred and cooled. The filtrate was cooled to 5-10°C. slowly and the resultant oxalate salt was filtered, dried at 60° C.and purified by dissolving in 420 ml acetone, heated to refluxtemperature, stirred to get clear solution, charcolized and distilled toa residual volume of 75 ml, cooled to 5-10° C. slowly and the resultantsolid was filtered, dried at 60° C. to get the oxalic acid salt of(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

Dry wt: 9.4 gm

[α]_(D)=+13.1° (c=1, methanol).

Chiral HPLC: R-isomer content: 1.04%.

Purity by HPLC: 99.59%.

Experiments A(2) and A(3) have been carried out in similar way as inExperiment No. A(1). Comparative Experiments A(1), A(2) and A(3) havebeen carried out according to the teaching of prior art, U.S. Pat. No.Re 34,712, which is incorporated herein by reference.

Experiment B(1):

To a solution of 16 gm of(S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethylbenzoate)-benzonitrilein 75 ml DMSO was added 19.3 gm of anhydrous K₂CO₃ and 10.8 gm of2,5-dichloronitrobenzene at room temperature and stirred for 15 hours at100-105° C. To the reaction mixture 750 ml of water was added at about30° C. The reaction mixture was extracted with toluene, the toluenelayer was washed with water and 5% sodium hydroxide solution and afteracid base treatment yielded an oily product. The oil was dissolved in amixture of 125 ml IPA and 5 ml water at 30° C. and 5.3 gm of oxalic aciddihydrate was added to it, heated to 70-75° C., stirred and charcolizedto get clear solution, cooled to 5-10° C. slowly and the resultantoxalate salt was filtered, dried at 60° C. and purified by dissolving ina mixture of 140 ml isopropanol and 5.6 ml water at 30° C. heated to70-75° C., stirred to get a clear solution, cooled to 5-10° C. slowlyand the resultant solid was filtered, dried at 60° C. to get the oxalicacid salt of(S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

Dry wt: 13.3 gm

[α]_(D)=+13.2° (c=1, methanol).

Chiral HPLC: R-isomer content: 0.34%.

Purity by HPLC: 99.76%.

Experiments B(2) and B(3) have been carried out in similar way as inExperiment No. B(1), which illustrate the process of the presentinvention.

It is evident from the data presented in Table I and the worked outexamples, that (S)-(+)-citalopram prepared by the process of the presentinvention contains R-isomer in the range of 0.00 to 0.38%, whereas(S)-(+)-citalopram prepared by the prior art process of methanesulfonylester derivative contains R-isomer in the range of 0.84 to 1.04%.

1. A compound of formula Va, or acid addition salt thereof,

wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which may be optionally substituted with electron withdrawing groups and Z is a cyano group or a group that may be converted to a cyano group.
 2. A compound of formula V, or acid addition salt thereof,

Formula V wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which may be optionally substituted with electron withdrawing groups.
 3. A process for preparation of a compound of formula Va, comprising reacting a compound of formula IVa, in the presence of a base with a compound of formula RX,

wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which may be optionally substituted with electron withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf represents trifluoromethanesulfonyl group, and R₁ is optionally substituted alkyl, Z is a cyano group or a group that may be converted to a cyano group.
 4. A process for preparation of a compound of formula V,

comprising reacting 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile, in the presence of a base, with a compound of formula RX, wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which may be optionally substituted with electron withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and OR₁, wherein Tf represents trifluoromethanesulfonyl group, and R₁ is optionally substituted alkyl.
 5. The compound as claimed in claim 1 or 2, which is 4-[4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)-benzonitrile, a compound of the following Formula VIII, or an acid addition salt thereof,


6. The compound as claimed in claim 1 or 2, which is (S)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(2-nitro-4-chlorophenoxymethyl)-benzonitrile, or an acid addition salt thereof.
 7. The hydrochloride salt of the compound as claimed in claim
 6. 